AIDS-related Kaposi's sarcoma (AIDS-KS) occurs in persons with HIV infection who are also infected with the Kaposi's sarcoma herpesvirus (KSHV). Several chemotherapy (anti-cancer) drugs work well in treating KS, but there is no treatment that cures KSHV infection. One chemotherapy drug called etoposide (VePesid®, ET) has caused KS tumors to get smaller in some people.

Antiretroviral therapy (anti-HIV drugs or ART) is a group of medicines taken together to treat HIV infection. These medicines help to stop HIV from growing in the body. When this happens, your immune system, which fights infection and some cancers like KS, will get stronger. For some people, limited stage KS often improves or stays the same when they take ART. However, in some people KS gets worse when taking ART. These people may need chemotherapy at a later date.

This study is being done to find out if taking ART with immediate etoposide (ET) is better than taking ART alone or ART with delayed ET to treat limited stage KS. The study will also try to better understand KSHV and to see what kind of side effects are caused by ART and ET and how safe ART and ET are.

KS treatment response is an ordinal composite measure with three categories defined as: failure (KS progression, initiation of a new chemotherapy agent other than ET, or no follow-up at week 48 including death and missed visit), stable (in follow-up at week 48 with no KS progression nor response and without initiation of a new chemotherapy other than ET) and response (in follow-up at week 48, with KS partial or complete response and without initiation of a new chemotherapy agent other than ET.

Partial response determined by clinician as no new oral lesions, visceral sites of involvement, appearance or worsening of tumor-associated edema or effusions, development of >=5 new cutaneous lesions in sites without cutaneous disease at entry and one or more of: 1) >=50% decrease in number of lesions 2) complete flattening of >=50% of all raised lesions 3) >=50% decrease in the area of the 5 cutaneous marker lesions, compared to entry.

Complete response determined by clinician as absence of any detectable residual KS disease, including tumor-associated edema.

Time from study treatment initiation to initial KS partial or complete response [ Time Frame: From study treatment initiation to 96 weeks ] [ Designated as safety issue: No ]

Partial response determined by clinician as no new oral lesions, visceral sites of involvement, appearance or worsening of tumor-associated edema or effusions, development of >=5 new cutaneous lesions in sites without cutaneous disease at entry and one or more of: 1) >=50% decrease in number of lesions 2) complete flattening of >=50% of all raised lesions 3) >=50% decrease in the area of the 5 cutaneous marker lesions, compared to entry. Complete response determined by clinician as absence of any detectable residual KS disease, including tumor-associated edema

Number of participants with KS partial response [ Time Frame: At weeks 48 and 96 ] [ Designated as safety issue: No ]

Partial response determined by clinician as no new oral lesions, visceral sites of involvement, appearance or worsening of tumor-associated edema or effusions, development of >=5 new cutaneous lesions in sites without cutaneous disease at entry and one or more of: 1) >=50% decrease in number of lesions 2) complete flattening of >=50% of all raised lesions 3) >=50% decrease in the area of the 5 cutaneous marker lesions, compared to entry.

Number of participants with KS complete response [ Time Frame: At weeks 48 and 96 ] [ Designated as safety issue: No ]

Complete response determined by clinician as absence of any detectable residual KS disease, including tumor-associated edema.

Number of participants with KS partial or complete response [ Time Frame: At weeks 48 and 96 ] [ Designated as safety issue: No ]

Partial response determined by clinician as no new oral lesions, visceral sites of involvement, appearance or worsening of tumor-associated edema or effusions, development of >=5 new cutaneous lesions in sites without cutaneous disease at entry and one or more of: 1) >=50% decrease in number of lesions 2) complete flattening of >=50% of all raised lesions 3) >=50% decrease in the area of the 5 cutaneous marker lesions, compared to entry. Complete response determined by clinician as absence of any detectable residual KS disease, including tumor-associated edema.

Number of participants with early study discontinuation [ Time Frame: At weeks 48 and 96 ] [ Designated as safety issue: No ]

Number of subjects who discontinued study prematurely due to any reason.

Time from initiation of delayed etoposide to initial KS partial response in Arm A [ Time Frame: From initiation of etoposide to 96 weeks ] [ Designated as safety issue: No ]

Participants will receive co-formulated efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). At the discretion of the site investigator, after confirmation of disease progression by the IERC (Independent Endpoint Review Committee), participants who experience KS progression in Arm A will receive ET in addition to EFV/FTC/TDF. ET can be offered in Step 2 to participants randomized to Arm A in Step 1 whose KS progresses.

50 mg taken orally daily from days 1-7 of each 2-week cycle. For participants without PR or CR after two cycles of therapy and no toxicity greater than Grade 2, the dose of ET will be escalated to 100 mg/day orally, days 1-7, every 2 weeks. A cycle can be delayed for a maximum of 14 days. ET must not be initiated prior to 7 days after the last dose in each cycle before starting the next cycle. ET may be administered up to a maximum of eight cycles (2 cycles during dose titration and 6 cycles at maximum dose). Participants who cannot tolerate escalation of the ET dose to 100 mg/day will be treated for a maximum of six cycles. Duration based on participant response to dosage.

50 mg taken orally daily from days 1-7 of each 2-week cycle. For participants without PR or CR after two cycles of therapy and no toxicity greater than Grade 2, the dose of ET will be escalated to 100 mg/day orally, days 1-7, every 2 weeks. A cycle can be delayed for a maximum of 14 days. ET must not be initiated prior to 7 days after the last dose in each cycle before starting the next cycle. ET may be administered up to a maximum of eight cycles (2 cycles during dose titration and 6 cycles at maximum dose). Participants who cannot tolerate escalation of the ET dose to 100 mg/day will be treated for a maximum of six cycles. Duration based on participant response to dosage.

Other Names:

VePesid®

ET

Eligibility

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Step 1: Inclusion Criteria

HIV-1 infection.

Biopsy diagnostic of KS at any time prior to study entry.

Current limited stage KS using the ACTG criteria documented in the study protocol. The following presentations of stage T1 KS are also eligible at the discretion of the site investigator:

Tumor-associated edema limited to the area(s) of KS without significant functional impairment.

Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to study entry.

All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).

Female participants who are participating in sexual activity that could lead to pregnancy must agree to use a combination of TWO of the following methods- Condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, IUD, and/or hormonal-based contraception.

For Etoposide, confirmation of lack of reproductive potential is required for all participants. More information on this criterion can be found in the study protocol.

Ability to swallow oral medications.

Karnofsky performance score >= 60 within 30 days prior to entry.

Ability and willingness of participant or legal guardian/representative to provide informed consent.

For treatment-experienced patients, the availability of an ART regimen that includes at least two ART drugs that in the opinion of the site investigator are expected to have activity based on historical genotypic testing (if available) and treatment history.

For participants who are to receive ART other than EFV/TDF/FTC, the availability of those ART components.

Step 2: Inclusion Criteria

KS progression as defined in the study protocol or KS progression after a complete or partial response as defined in the study protocol, while on Step 1 Arm 1A, between weeks 8 and 80.

Need for ET for treatment of KS progression, in the opinion of the site investigator, after confirmation of KS progression by the IERC.

Willingness to receive ET for treatment of KS progression.

Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to initiating ET.

All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).

Female participants who are participating in sexual activity that could lead to pregnancy must agree to use a combination of TWO of the following methods- Condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, IUD, hormonal-based contraception.

For Etoposide, confirmation of lack of reproductive potential is required for all participants. More information on this criterion can be found in the study protocol.

Step 3: Inclusion Criteria

1. Received at least one dose of ET (Arm 1B or Arm 2A)

Step 1: Exclusion Criteria

Any manifestation of KS which, in the opinion of the site investigator, requires immediate chemotherapy.

Any prior local treatment of cutaneous marker lesions unless there was evidence of a clear-cut progression of the lesion.

Receipt of any investigational therapy within 30 days prior to study entry.

Current or anticipated receipt of any of the prohibited medications indicated in the PSWP.

In the opinion of the site investigator, any psychological or social condition, or addictive disorder that would preclude compliance with the protocol.

Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to study entry and/or is not clinically stable.

Step 2: Exclusion Criteria

Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to initiating ET and/or is not clinically stable.

Current or anticipated receipt of any of the prohibited medications indicated in the PSWP.

Breastfeeding.

There are no exclusion criteria for Step 3.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01352117